BLAST: Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL)

• Sponsor: Amgen Research (Munich) GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01207388
• Collaborator: (none)
• Enrollment: 116
• Locations: 75
• Arm: 1
• Duration (Months): 98.2
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to confirm whether the bispecific T cell engager blinatumomab (MT103) is effective, safe and tolerable in the treatment of ALL patients with minimal residual disease.

Condition or Disease	Intervention/Treatment	Phase
B-cell Acute Lymphoblastic Leukemia	Drug: Blinatumomab	Phase 2

Detailed Description

The detection of minimal residual disease (MRD) after induction therapy and/or consolidation therapy is an independent prognostic factor for poor outcome of adult ALL. No standard treatments are available for patients with MRD-positive B-precursor ALL. Blinatumomab (MT103) is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T-cell activation and a cytotoxic T-cell response against cluster of differentiation (CD)19 expressing cells. The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab (MT103) is effective, safe and tolerable in the treatment of ALL patients with minimal residual disease.

Participants will receive up to four 4-week cycles of intravenous blinatumomab treatment followed by an infusion-free period of 14 days. A safety follow-up will be performed 30 days after the end of the last infusion and efficacy follow-ups will occur until 24 months after treatment start. Participants will be followed for up to 5 years after the start of treatment for survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Confirmatory Multicenter, Single-arm Study to Assess the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (BLAST)
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Jan 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Blinatumomab Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.	Drug: Blinatumomab; Continuous intravenous infusion; Other Names: AMG 103 MT103 BLINCYTO™

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Minimal Residual Disease (MRD) Response Within the First Treatment Cycle [During the first cycle (6 weeks)]

   At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. Complete MRD response is defined as no polymerase chain reaction (PCR) amplification of individual rearrangements of immunoglobulin (Ig)- or T-cell receptor (TCR)-genes detected after completion of the first cycle.

Secondary Outcome Measures

1. Hematological Relapse-free Survival (RFS) [18 months, up to the data cut-off date of 05 August 2015]

   Hematological RFS was measured from first dose of blinatumomab until the first assessment of documented relapse (either hematological or extramedullary), secondary leukemia, or death due to any cause. Participants without a documented relapse, or death due to any cause were censored at the time of their last hematological assessment. Participants who received chemotherapy for relapsed or persistent MRD or for any other reason after treatment with blinatumomab, or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse, or death occurred were censored at the start of chemotherapy or HSCT, respectively. Hematological relapse was defined as unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological, microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia (whichever occurred first). The 18-month Kaplan-Meier estimate of hematological RFS is reported.

2. Overall Survival [Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.]

   Overall survival was measured from the first treatment with blinatumomab until death due to any cause. Participants who did not die were censored at their last contact date.

3. 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant [100 days after HSCT, as of the data cut-off date of 05 August 2015]

   The mortality rate within 100 days after allogeneic HSCT was defined as the Kaplan-Meier estimate of the percentage of participants dying within 100 days after the day of the first allogeneic HSCT.

4. Time to Hematological Relapse [Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.]

   Time to hematological relapse was measured from the start of treatment with blinatumomab until hematological or extramedullary relapse. Participants who died or received HSCT or post-blinatumomab chemotherapy after treatment with blinatumomab were censored at their last hematological assessment prior to death or HSCT or post-blinatumomab chemotherapy (whichever occurred first).

5. Duration of Complete MRD Response [Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.]

   The duration of MRD response was analyzed as the time from onset of MRD negativity until MRD or hematological relapse or date of last confirmation of negative MRD status. Participants who received chemotherapy or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse were censored at the start of chemotherapy or HSCT, respectively. MRD relapse is defined as the reappearance of individual rearrangements of Ig- or TCR-genes ≥ lower limit of quantification (LLOQ) for at least 1 individual marker measured by an assay with a sensitivity of minimum 10^-4. Hematological relapse is defined as the unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological or microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia.

6. Change in MRD Level From Baseline to End of Cycle 1 in Non-MRD Responders [Baseline and end of cycle 1 (6 weeks)]

   MRD level was measured by polymerase chain reaction (PCR) performed on bone marrow and assessed by the central laboratory. An MRD level of 10^-n corresponds to residual leukemia cells at a frequency of 1 per 10ⁿ bone marrow cells.

7. Number of Participants With Adverse Events [From the first dose of blinatumomab until 30 days after last dose; the median treatment duration was 55 days.]

   Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.

8. Change From Baseline in EORTC-QLQ-C30 Scales [Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).]

   The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact). For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms. The maximum changes from baseline to cycles 1 through 4 and the change from baseline to the end of the core study are reported.

9. Change From Baseline in EuroQoL 5-Dimension (EQ-5D) Scales [Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).]

   The EQ-5D is a self-administered questionnaire which captures 3 basic types of information: a descriptive profile (health state index) and the overall health rating using a visual analog scale. The health state index measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression on scales from no problems (score = 1), some problems (score = 2), to extreme problems (score = 3). For each dimension the mean change from baseline was calculated at the end of each treatment cycle and at the end of the core study. The maximum observed change from baseline during cycles 1 to 4 and the change from baseline at the end of the core study are reported for each dimension.

10. Resource Utilization: Number of Participants Reporting Use of Transfusion of Blood Products [From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months]

11. Resource Utilization: Duration of Hospitalization [From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with B-precursor ALL in complete hematological remission after at least 3 intense chemotherapy blocks

• Presence of minimal residual disease at a level of ≥ 10^-3

• Availability of bone marrow specimen from primary diagnosis for clone-specific MRD assessment

• Negative human immunodeficiency virus (HIV) test, negative hepatitis B (HbsAg) test and hepatitis C virus (anti-HCV) test

• Negative pregnancy test in women of childbearing potential

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

• Presence of circulating blasts or current extra-medullary involvement by ALL

• History of relevant central nervous system (CNS) pathology or current CNS pathology

• Prior allogeneic hematopoietic stem cell transplant (HSCT)

• Eligibility for treatment with tyrosine-kinase inhibitors (TKI)

• Systemic cancer chemotherapy within 2 weeks prior to study treatment

• Therapy with monoclonal antibodies (rituximab, alemtuzumab) within 4 weeks prior to study treatment

• Previous treatment with blinatumomab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1102 - LKH Graz	Graz		Austria
2	1107 - Krankenhaus der Elisabethinen	Linz		Austria
3	1106	Salzburg		Austria
4	1101 - AKH Wien	Vienna		Austria
5	1504	Antwerpen		Belgium
6	1502 - Cliniques Universitaires de Saint-Luc	Brussels		Belgium
7	1505	Brügge		Belgium
8	1503	Gent		Belgium
9	1501 - Cliniques Universitaires UCL de Mont Godinne	Yvoir		Belgium
10	1211 - CHU d'Angers	Angers		France
11	1210 - CHU de Besançon	Besançon		France
12	1206 - Hôpital de Pontoise	Cergy Pontoise		France
13	1205 - CHU Henri Mondor	Créteil		France
14	1209 - CHU de Lyon	Lyon		France
15	1212 - Hôpital de l'hôtel Dieu	Nantes		France
16	1213 - Centre Hospitalier Universitaire de Nice	Nice		France
17	1201 - Hôpital Saint Louis	Paris		France
18	1202 - CHU de Bordeaux - Hôpital Haut Lévêque	Pessac		France
19	1208 - CHU de Purpan	Toulouse		France
20	1011 - Charité Berlin	Berlin		Germany
21	1022 - Universitätsklinkum Carl Gustav Carus Dresden	Dresden		Germany
22	1009 - Universitätsklinikum Essen	Essen		Germany
23	1002 - Klinikum der Goethe Universität	Frankfurt		Germany
24	1014 - Asklepiosklinik St. Georg	Hamburg		Germany
25	1018 - Medizinische Hochschule Hannover	Hannover		Germany
26	1012 - Universitätsklinikum Heidelberg	Heidelberg		Germany
27	1003 - Universitätsklinikum Schleswig-Holstein	Kiel		Germany
28	1019 - Universitätsklinikum Leipzig	Leipzig		Germany
29	1010 - Klinikum der Universität München - Großhadern	Munich		Germany
30	1004 - Universitätsklinikum Münster	Münster		Germany
31	1016 - Universitätsklinikum Regensburg	Regensburg		Germany
32	1020 - Universitätsklinikum Rostock	Rostock		Germany
33	1007 - Robert-Bosch-Krankenhaus	Stuttgart		Germany
34	1015 - Universitätsklinikum Tübingen	Tübingen		Germany
35	1005 - Universitätsklinikum Ulm	Ulm		Germany
36	1001 - Julius-Maximilians-Universität Würzburg	Würzburg		Germany
37	1301 - Ospedali Riuniti di Bergamo	Bergamo		Italy
38	1303 - Istituto di Ematologia "L.& A.Seràgnoli" Azienda	Bologna		Italy
39	1314 - Azienda Ospedaliera Spedali Civili Brescia	Brescia		Italy
40	1313 - Universita di Catania	Catania		Italy
41	1312 - Azienda Ospedaliera Universitaria San Martino	Genoa		Italy
42	1305 - Ospedale San Gerardo	Monza		Italy
43	1309 - Azienda Ospedaliera Antonio Cardarelli	Napoli		Italy
44	1308 - Ospedali Riuniti "Villa Sofia-Cervello"	Palermo		Italy
45	1302 - Università La Sapienza di Roma	Rome		Italy
46	1310 - Fondazione Policlinico Tor Vergata	Rome		Italy
47	1315 - Azienda Ospedaliero-Universitaria S. Giovanni Battista (Le Molinette)	Torino		Italy
48	1311 - Azienda Ospedaliera di Verona	Verona		Italy
49	2204 - UMC Groningen	Groningen		Netherlands
50	2201 - Daniel Den Hoed Hospitaal	Rotterdam		Netherlands
51	1905 - Uniwersytecki Szpital Kliniczny w Białymstoku	Bialystok		Poland
52	1907 - Uniwersyteckie Centrum Kliniczne	Gdansk		Poland
53	1908 - Swietokrzyskie Centrum Onkologii	Kielce		Poland
54	1902 - Uniwersytet Medyczny w Lublinie	Lublin		Poland
55	1901 - Klinika Hematologii - Instytut Hematologii i Transfuzjologii	Warsaw		Poland
56	1906 - MTZ Clinical Research Sp. z o.o.	Warsaw		Poland
57	1904 - Samodzielny Publiczny	Wrocław		Poland
58	2101 - Institutul Clinic Fundeni, Hematologie II	Bucharest		Romania
59	2102 - Spitalul Clinic Coltea, Hematologie	Bucharest		Romania
60	2106 - Institutul Oncologic "Prof. Dr. I. Chiricuta"	Cluj-Napoca		Romania
61	2105 - Institutul Regional de Oncologie	Iasi		Romania
62	2001 - Russian Hematology Research Center	Moscow		Russian Federation
63	2003 - Municipal Hospital No. 15	St. Petersburg		Russian Federation
64	1401 - ICO Hospital Germans Trias I Pujol	Badalona		Spain
65	1404 - Hospital Clínic Servei d´Hematologia	Barcelona		Spain
66	1402 - Complexo Hospitalario Universitario A Coruña	La Coruña		Spain
67	1408 - Hospital 12 de Octubre	Madrid		Spain
68	1405 - Hospital Universitari Son Espases	Mallorca		Spain
69	1407 - Unidad de Citogenética Oncológica	Salamanca		Spain
70	1406 - Hospital Universitari i Politècnic La Fe de Valencia	Valencia		Spain
71	1605 - Queen Elizabeth Hospital	Birmingham		United Kingdom
72	1602 - Bristol Royal Infirmary	Bristol		United Kingdom
73	1604 - University Hospital of Wales	Cardiff		United Kingdom
74	1601 - Royal Free Hospital	London		United Kingdom
75	1607 - Nottingham City Hospital NHS Trust	Nottingham		United Kingdom

Sponsors and Collaborators

• Amgen Research (Munich) GmbH

Investigators

• Principal Investigator: Ralf Bargou, MD, Medizinische Klinik und Poliklinik II, Würzburg
• Principal Investigator: Nicola Gökbuget, MD, Klinikum der Goethe Universität Frankfurt

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amgen Research (Munich) GmbH
• ClinicalTrials.gov Identifier: NCT01207388
• Other Study ID Numbers: MT103-203
• First Posted: Sep 22, 2010
• Last Update Posted: Feb 10, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by Amgen Research (Munich) GmbH: Blinatumomab; MRD; B-ALL; Minimal residual disease; adult ALL; Leukemia; ALL; Lymphatic diseases; Lymphoproliferative disorders; bispecific antibody; anti-CD19; Immunotherapeutic treatment
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Neoplasm, Residual; Blinatumomab

Study Results

Participant Flow

Recruitment Details	This study was open to adults with a diagnosis of minimal residual disease (MRD; ≥ 10-³ leukemic cells) -positive B-precursor acute lymphoblastic leukemia (ALL) who were in complete hematologic remission.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment. Participants suitable for allogeneic hematopoietic stem cell transplant (HSCT) after treatment with at least 1 cycle of blinatumomab may have undergone allogeneic HSCT instead of receiving further cycles with blinatumomab.
Period Title: Overall Study
STARTED	116
COMPLETED	48
NOT COMPLETED	68

Baseline Characteristics

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Overall Participants	116
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.6 (16.4)
Age, Customized (participants) [Number]
≥ 18 and <35 years	36 31%
≥ 35 and < 55 years	41 35.3%
≥ 55 and < 65 years	24 20.7%
≥ 65 years	15 12.9%
Sex: Female, Male (Count of Participants)
Female	48 41.4%
Male	68 58.6%
Race/Ethnicity, Customized (participants) [Number]
White	102 87.9%
Asian	1 0.9%
Mixed	1 0.9%
Unknown	12 10.3%
Philadelphia Chromosome Disease Status (participants) [Number]
Positive	5 4.3%
Negative	111 95.7%
Confirmed t(4;11) Translocation / MLL-AF4+ ALL (Count of Participants)
Yes	5 4.3%
No	88 75.9%
Unknown	23 19.8%
MRD Level at Baseline by Central Laboratory (participants) [Number]
≥ 10^-1 and < 1	9 7.8%
≥ 10^-2 and < 10^-1	45 38.8%
≥ 10^-3 and < 10^-2	52 44.8%
< 10^-3	3 2.6%
Below Lower Limit of Quantification	5 4.3%
Unknown	2 1.7%
White Blood Cells at First Diagnosis (participants) [Number]
≤ 30,000/mL	78 67.2%
> 30,000/mL	18 15.5%
Unknown	20 17.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Minimal Residual Disease (MRD) Response Within the First Treatment Cycle
Description	At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. Complete MRD response is defined as no polymerase chain reaction (PCR) amplification of individual rearrangements of immunoglobulin (Ig)- or T-cell receptor (TCR)-genes detected after completion of the first cycle.
Time Frame	During the first cycle (6 weeks)

Outcome Measure Data

Analysis Population Description

Primary endpoint full analysis set (Prim EP FAS) included all participants with an Ig TCR PCR MRD assay with the minimum required sensitivity of 1 x 10^-4 at central lab established at Baseline.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	113
Number (95% Confidence Interval) [percentage of participants]	77.0 66.4%

2. Secondary Outcome

Title	Hematological Relapse-free Survival (RFS)
Description	Hematological RFS was measured from first dose of blinatumomab until the first assessment of documented relapse (either hematological or extramedullary), secondary leukemia, or death due to any cause. Participants without a documented relapse, or death due to any cause were censored at the time of their last hematological assessment. Participants who received chemotherapy for relapsed or persistent MRD or for any other reason after treatment with blinatumomab, or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse, or death occurred were censored at the start of chemotherapy or HSCT, respectively. Hematological relapse was defined as unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological, microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia (whichever occurred first). The 18-month Kaplan-Meier estimate of hematological RFS is reported.
Time Frame	18 months, up to the data cut-off date of 05 August 2015

Outcome Measure Data

Analysis Population Description

Full analysis set participants who were in hematological complete remission at treatment start, excluding Philadelphia-positive participants.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	110
Number (95% Confidence Interval) [percentage of participants]	54 46.6%

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival was measured from the first treatment with blinatumomab until death due to any cause. Participants who did not die were censored at their last contact date.
Time Frame	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	116
Median (95% Confidence Interval) [months]	36.5

4. Secondary Outcome

Title	100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
Description	The mortality rate within 100 days after allogeneic HSCT was defined as the Kaplan-Meier estimate of the percentage of participants dying within 100 days after the day of the first allogeneic HSCT.
Time Frame	100 days after HSCT, as of the data cut-off date of 05 August 2015

Outcome Measure Data

Analysis Population Description

Full analysis set participants who underwent HSCT prior to relapse (hematological or extramedullary) excluding Philadelphia-positive participants

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	74
Number (95% Confidence Interval) [percentage of participants]	7 6%

5. Secondary Outcome

Title	Time to Hematological Relapse
Description	Time to hematological relapse was measured from the start of treatment with blinatumomab until hematological or extramedullary relapse. Participants who died or received HSCT or post-blinatumomab chemotherapy after treatment with blinatumomab were censored at their last hematological assessment prior to death or HSCT or post-blinatumomab chemotherapy (whichever occurred first).
Time Frame	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.

Outcome Measure Data

Analysis Population Description

Full analysis set participants who were in hematological complete remission at treatment start, excluding Philadelphia-positive participants.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	110
Median (95% Confidence Interval) [months]	NA

6. Secondary Outcome

Title	Duration of Complete MRD Response
Description	The duration of MRD response was analyzed as the time from onset of MRD negativity until MRD or hematological relapse or date of last confirmation of negative MRD status. Participants who received chemotherapy or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse were censored at the start of chemotherapy or HSCT, respectively. MRD relapse is defined as the reappearance of individual rearrangements of Ig- or TCR-genes ≥ lower limit of quantification (LLOQ) for at least 1 individual marker measured by an assay with a sensitivity of minimum 10^-4. Hematological relapse is defined as the unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological or microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia.
Time Frame	Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.

Outcome Measure Data

Analysis Population Description

Full analysis set participants who were in hematological complete remission at treatment start, excluding Philadelphia-positive participants, who had an MRD complete response at cycle 1

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	85
Median (95% Confidence Interval) [months]	45.0

7. Secondary Outcome

Title	Change in MRD Level From Baseline to End of Cycle 1 in Non-MRD Responders
Description	MRD level was measured by polymerase chain reaction (PCR) performed on bone marrow and assessed by the central laboratory. An MRD level of 10^-n corresponds to residual leukemia cells at a frequency of 1 per 10ⁿ bone marrow cells.
Time Frame	Baseline and end of cycle 1 (6 weeks)

Outcome Measure Data

Analysis Population Description

Full analysis set participants who were in hematological complete remission at treatment start, with no MRD Response in the first treatment cycle, excluding Philadelphia-positive participants.

Arm/Group Title	Cycle 1 MRD 10^-5	Cycle 1 MRD 10^-4	Cycle 1 MRD 10^-3	Cycle 1 MRD 10^-2	Cycle 1 MRD 10^-1	Cycle 1 MRD Unknown
Arm/Group Description	Participants with an MRD level 10^-5 at the end of cycle 1.	Participants with an MRD level 10^-4 at the end of cycle 1.	Participants with an MRD level 10^-3 at the end of cycle 1.	Participants with an MRD level 10^-2 at the end of cycle 1.	Participants with an MRD level 10^-1 at the end of cycle 1.	Participants with an unknown MRD level at the end of cycle 1.
Measure Participants	2	13	4	0	2	2
Baseline MRD Unknown	0 0%	1 NaN	0 NaN	0 NaN	0 NaN
Baseline MRD 10^-5	0 0%	0 NaN	0 NaN	0 NaN	0 NaN
Baseline MRD 10^-4	0 0%	1 NaN	0 NaN	0 NaN	0 NaN
Baseline MRD 10^-3	1 0.9%	6 NaN	2 NaN	1 NaN	0 NaN
Baseline MRD 10^-2	0 0%	5 NaN	2 NaN	1 NaN	0 NaN
Baseline MRD 10^-1	1 0.9%	0 NaN	0 NaN	0 NaN	2 NaN

8. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.
Time Frame	From the first dose of blinatumomab until 30 days after last dose; the median treatment duration was 55 days.

Outcome Measure Data

Analysis Population Description

All participants who received any infusion of blinatumomab.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	116
Any adverse event	116 100%
Serious adverse events	73 62.9%
Adverse events ≥ CTC grade 3	71 61.2%
Adverse events ≥ CTC grade 4	33 28.4%
Fatal adverse events	2 1.7%
AEs leading to discontinuation of blinatumomab	20 17.2%
AEs leading to interruption of blinatumomab	36 31%
Treatment-related adverse events	112 96.6%
Treatment-related serious adverse events	60 51.7%
Treatment-related adverse events ≥ CTC grade 3	60 51.7%
Treatment-related adverse events ≥ CTC grade 4	26 22.4%
Treatment-related fatal adverse events	1 0.9%

9. Secondary Outcome

Title	Change From Baseline in EORTC-QLQ-C30 Scales
Description	The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact). For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms. The maximum changes from baseline to cycles 1 through 4 and the change from baseline to the end of the core study are reported.
Time Frame	Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).

Outcome Measure Data

Analysis Population Description

FAS with available data at relevant time points. For maximum change, the change from baseline was calculated using subset of FAS with available data (baseline and post-baseline) at the end of each cycle. The number analyzed are the number of subjects with available data at the time point at which maximum change from baseline was observed.

Arm/Group Title	Maximum Change From Baseline in Cycles 1 - 4	Change From Baseline at End of Core Study
Arm/Group Description
Measure Participants	111	74
Global Health Status	9.0 (4.2)	3.9 (2.4)
Physical Functioning	2.6 (2.3)	2.2 (1.9)
Role Functioning	12.2 (8.5)	1.4 (3.5)
Emotional Functioning	6.5 (4.9)	5.3 (2.7)
Cognitive Functioning	-3.3 (5.2)	-2.3 (2.5)
Social Functioning	12.2 (8.5)	14.9 (3.8)
Fatigue Symptom	-5.9 (5.5)	-5.4 (2.4)
Nausea and Vomiting Symptom	-4.5 (4.7)	-2.3 (2.0)
Pain Symptom	3.8 (3.6)	-1.4 (2.7)
Dyspnea Symptom	-9.0 (4.7)	-0.9 (2.9)
Insomnia Symptom	-2.6 (3.2)	3.7 (3.5)
Appetite Loss Symptom	-17.8 (6.4)	-9.1 (3.4)
Constipation Symptom	-5.1 (3.6)	0.0 (2.2)
Diarrhea Symptom	5.1 (5.5)	0.0 (2.3)
Financial Difficulties Symptom	-5.1 (4.8)	-0.9 (2.9)

10. Secondary Outcome

Title	Change From Baseline in EuroQoL 5-Dimension (EQ-5D) Scales
Description	The EQ-5D is a self-administered questionnaire which captures 3 basic types of information: a descriptive profile (health state index) and the overall health rating using a visual analog scale. The health state index measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression on scales from no problems (score = 1), some problems (score = 2), to extreme problems (score = 3). For each dimension the mean change from baseline was calculated at the end of each treatment cycle and at the end of the core study. The maximum observed change from baseline during cycles 1 to 4 and the change from baseline at the end of the core study are reported for each dimension.
Time Frame	Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).

Outcome Measure Data

Analysis Population Description

FAS with available data at relevant time points. For maximum change, the change from baseline was calculated using subset of FAS with available data (baseline and post-baseline) at the end of each cycle. The number analyzed are the number of subjects with available data at the time point at which maximum change from baseline was observed.

Arm/Group Title	Maximum Change From Baseline in Cycles 1 - 4	Change From Baseline at End of Core Study
Arm/Group Description
Measure Participants	112	75
Mobility	-0.2 (0.1)	0.0 (0.1)
Self-care	-0.1 (0.1)	0.0 (0.0)
Usual Activities	-0.1 (0.1)	-0.1 (0.1)
Pain/Discomfort	-0.2 (0.2)	-0.1 (0.1)
Anxiety/Depression	-0.2 (0.1)	-0.1 (0.1)

11. Secondary Outcome

Title	Resource Utilization: Number of Participants Reporting Use of Transfusion of Blood Products
Time Frame	From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	116
Overall	14 12.1%
Cycle 1	5 4.3%
Cycle 2	8 6.9%
Cycle 3	0 0%
Cycle 4	1 0.9%
Follow-up period	0 0%

12. Secondary Outcome

Title	Resource Utilization: Duration of Hospitalization
Time Frame	From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Measure Participants	116
Median (Full Range) [days]	14.0

Adverse Events

Time Frame	All-cause mortality is reported from enrollment until the end of the follow-up period; median (minimum, maximum) time on study was 33.8 (1, 62) months. Adverse events are reported from the first dose of blinatumomab until 30 days after last dose; the median treatment duration was 55 days.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
All Cause Mortality
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	67/116 (57.8%)
Serious Adverse Events
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	73/116 (62.9%)
Blood and lymphatic system disorders
Anaemia	1/116 (0.9%)
Bone marrow failure	1/116 (0.9%)
Febrile neutropenia	2/116 (1.7%)
Leukopenia	1/116 (0.9%)
Neutropenia	5/116 (4.3%)
Thrombocytopenia	1/116 (0.9%)
Cardiac disorders
Sinus bradycardia	1/116 (0.9%)
Sinus tachycardia	1/116 (0.9%)
Gastrointestinal disorders
Abdominal pain	1/116 (0.9%)
Diarrhoea	1/116 (0.9%)
Gastrointestinal haemorrhage	1/116 (0.9%)
General disorders
Device issue	1/116 (0.9%)
Device malfunction	2/116 (1.7%)
Fatigue	1/116 (0.9%)
Gait disturbance	1/116 (0.9%)
Infusion site extravasation	1/116 (0.9%)
Product contamination microbial	1/116 (0.9%)
Puncture site pain	1/116 (0.9%)
Pyrexia	17/116 (14.7%)
Thrombosis in device	1/116 (0.9%)
Hepatobiliary disorders
Hepatotoxicity	1/116 (0.9%)
Immune system disorders
Cytokine release syndrome	2/116 (1.7%)
Hypersensitivity	2/116 (1.7%)
Infections and infestations
Acinetobacter bacteraemia	1/116 (0.9%)
Atypical pneumonia	1/116 (0.9%)
Bacterial infection	1/116 (0.9%)
Bronchopneumonia	1/116 (0.9%)
Bronchopulmonary aspergillosis	1/116 (0.9%)
Cystitis klebsiella	1/116 (0.9%)
Device related infection	3/116 (2.6%)
H1N1 influenza	1/116 (0.9%)
Osteomyelitis	1/116 (0.9%)
Sepsis	1/116 (0.9%)
Sinusitis	2/116 (1.7%)
Staphylococcal infection	3/116 (2.6%)
Upper respiratory tract infection	1/116 (0.9%)
Urinary tract infection staphylococcal	1/116 (0.9%)
Injury, poisoning and procedural complications
Accidental overdose	1/116 (0.9%)
Incision site haemorrhage	1/116 (0.9%)
Infusion related reaction	1/116 (0.9%)
Overdose	5/116 (4.3%)
Post lumbar puncture syndrome	1/116 (0.9%)
Spinal fracture	1/116 (0.9%)
Subdural haemorrhage	1/116 (0.9%)
Thermal burn	1/116 (0.9%)
Investigations
Alanine aminotransferase increased	2/116 (1.7%)
Aspartate aminotransferase increased	2/116 (1.7%)
Blood bilirubin increased	1/116 (0.9%)
Body temperature increased	1/116 (0.9%)
C-reactive protein increased	4/116 (3.4%)
Hepatic enzyme increased	1/116 (0.9%)
Liver function test abnormal	1/116 (0.9%)
Prothrombin time prolonged	1/116 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Kaposi's sarcoma	1/116 (0.9%)
Leukaemia	1/116 (0.9%)
Nervous system disorders
Aphasia	6/116 (5.2%)
Ataxia	2/116 (1.7%)
Cognitive disorder	1/116 (0.9%)
Dysarthria	1/116 (0.9%)
Encephalopathy	6/116 (5.2%)
Generalised tonic-clonic seizure	1/116 (0.9%)
Headache	2/116 (1.7%)
Intention tremor	1/116 (0.9%)
Leukoencephalopathy	1/116 (0.9%)
Motor dysfunction	1/116 (0.9%)
Paraesthesia	1/116 (0.9%)
Seizure	3/116 (2.6%)
Tremor	8/116 (6.9%)
Psychiatric disorders
Agitation	1/116 (0.9%)
Confusional state	1/116 (0.9%)
Disorientation	1/116 (0.9%)
Skin and subcutaneous tissue disorders
Dermatitis contact	1/116 (0.9%)
Rash maculo-papular	1/116 (0.9%)
Vascular disorders
Hypotension	1/116 (0.9%)
Thrombosis	1/116 (0.9%)
Vena cava thrombosis	1/116 (0.9%)
Other (Not Including Serious) Adverse Events
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	111/116 (95.7%)
Blood and lymphatic system disorders
Anaemia	6/116 (5.2%)
Leukopenia	7/116 (6%)
Neutropenia	14/116 (12.1%)
Gastrointestinal disorders
Constipation	13/116 (11.2%)
Diarrhoea	22/116 (19%)
Nausea	27/116 (23.3%)
Vomiting	26/116 (22.4%)
General disorders
Chills	30/116 (25.9%)
Fatigue	27/116 (23.3%)
Pyrexia	99/116 (85.3%)
Infections and infestations
Device related infection	6/116 (5.2%)
Nasopharyngitis	8/116 (6.9%)
Investigations
Blood immunoglobulin G decreased	6/116 (5.2%)
C-reactive protein increased	6/116 (5.2%)
Weight increased	7/116 (6%)
Metabolism and nutrition disorders
Hypokalaemia	18/116 (15.5%)
Hypomagnesaemia	6/116 (5.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	15/116 (12.9%)
Back pain	10/116 (8.6%)
Pain in extremity	8/116 (6.9%)
Nervous system disorders
Aphasia	9/116 (7.8%)
Dizziness	9/116 (7.8%)
Headache	44/116 (37.9%)
Paraesthesia	6/116 (5.2%)
Tremor	28/116 (24.1%)
Psychiatric disorders
Insomnia	17/116 (14.7%)
Respiratory, thoracic and mediastinal disorders
Cough	15/116 (12.9%)
Skin and subcutaneous tissue disorders
Night sweats	7/116 (6%)
Rash	11/116 (9.5%)
Vascular disorders
Hypertension	7/116 (6%)
Hypotension	13/116 (11.2%)

Limitations/Caveats

[Not Specified]

More Information

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Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.